@article{98744a4c2b584d93a601abbbf2019e76,
title = "Proton extrusion during oxidative burst in microglia exacerbates pathological acidosis following traumatic brain injury",
abstract = "Acidosis is among the least studied secondary injury mechanisms associated with neurotrauma. Acute decreases in brain pH correlate with poor long-term outcome in patients with traumatic brain injury (TBI), however, the temporal dynamics and underlying mechanisms are unclear. As key drivers of neuroinflammation, we hypothesized that microglia directly regulate acidosis after TBI, and thereby, worsen neurological outcomes. Using a controlled cortical impact model in adult male mice we demonstrate that intracellular pH in microglia and extracellular pH surrounding the lesion site are significantly reduced for weeks after injury. Microglia proliferation and production of reactive oxygen species (ROS) were also increased during the first week, mirroring the increase in extracellular ROS levels seen around the lesion site. Microglia depletion by a colony stimulating factor 1 receptor (CSF1R) inhibitor, PLX5622, markedly decreased extracellular acidosis, ROS production, and inflammation in the brain after injury. Mechanistically, we identified that the voltage-gated proton channel Hv1 promotes oxidative burst activity and acid extrusion in microglia. Compared to wildtype controls, microglia lacking Hv1 showed reduced ability to generate ROS and extrude protons. Importantly, Hv1-deficient mice exhibited reduced pathological acidosis and inflammation after TBI, leading to long-term neuroprotection and functional recovery. Our data therefore establish the microglial Hv1 proton channel as an important link that integrates inflammation and acidosis within the injury microenvironment during head injury.",
keywords = "acidosis, chronic neurodegeneration, microglia, neuroinflammation, traumatic brain injury",
author = "Ritzel, {Rodney M.} and Junyun He and Yun Li and Tuoxin Cao and Niaz Khan and Bosung Shim and Boris Sabirzhanov and Taryn Aubrecht and Stoica, {Bogdan A.} and Faden, {Alan I.} and Wu, {Long Jun} and Junfang Wu",
note = "Funding Information: The author(s) disclosed receipt of the following financial support for the research, authorship, and/or publication of this article. The work was supported by the National Institutes of Health Grants R01 NS110825 (JW/LJW), R01 NS094527 (JW), 2R01 NR013601 (JW/AIF), R01 NS110635 (JW/AIF), R01 NS110567 (JW), RF1 NS110637 (JW), R01 NS088627 (LJW), F32 NS105355 (RMR), and K99 NS116032 (RMR). The authors thank Plexxikon Inc. (Berkeley, CA) for kindly providing us with PLX5622. The authors would also like to thank Hui Li and Lulu Liu for assisting in the mice perfusion, brain sectioning, and Y‐maze test; Jordan Carter and Courtney Colson for assistance with sample collection on acidosis assay and the cytometer; Xiaoxun Fan for assistance with flow cytometry. Funding Information: The author(s) disclosed receipt of the following financial support for the research, authorship, and/or publication of this article. The work was supported by the National Institutes of Health Grants R01 NS110825 (JW/LJW), R01 NS094527 (JW), 2R01 NR013601 (JW/AIF), R01 NS110635 (JW/AIF), R01 NS110567 (JW), RF1 NS110637 (JW), R01 NS088627 (LJW), F32 NS105355 (RMR), and K99 NS116032 (RMR). The authors thank Plexxikon Inc. (Berkeley, CA) for kindly providing us with PLX5622. The authors would also like to thank Hui Li and Lulu Liu for assisting in the mice perfusion, brain sectioning, and Y-maze test; Jordan Carter and Courtney Colson for assistance with sample collection on acidosis assay and the cytometer; Xiaoxun Fan for assistance with flow cytometry. Publisher Copyright: {\textcopyright} 2020 The Authors. GLIA published by Wiley Periodicals LLC",
year = "2021",
month = mar,
doi = "10.1002/glia.23926",
language = "English (US)",
volume = "69",
pages = "746--764",
journal = "GLIA",
issn = "0894-1491",
publisher = "John Wiley and Sons Inc.",
number = "3",
}